The candidate received a Ph.D. in Biochemistry in 1984. His thesis and research training were within the fields of protein chemistry and molecular biology (prokaryotic system). The candidate has recently attained his first academic position and wishes to pursue an academic career as an independent investigator. However, eleven years have elapsed since obtaining his Ph.D. and completion of medical school, residency, and subspecialty training (June 1994). Over this past decade, logarithmic advances within molecular biology and clinical genetics have occurred. Therefore to develop the techniques, skills, and publication record required of an independent investigator, the candidate will require additional training, guidance, and development. The candidate plans to obtain these necessary attributes (under the guidance of appropriate sponsors and collaborators) by hands on experience within the laboratory, additional course work, manuscript and grant preparation, attendance and presentation at relevant national meetings, and interactions with other basic scientists. The current proposal focuses on the well-recognized variability of familial hypertrophic cardiomyopathy (FHCM). More specifically, this proposal will test the hypothesis that various "asymptomatic" alleles of sarcomeric genes modulate the expression of the FHCM mutation and thus explain the variable expressivity of FHCM. Towards this goal, three specific aims have been outlined: 1) identification of FHCM loci 2) Molecular characterization of FHCM mutations and 3) localization and identification of modifier loci for FHCM. The proposal will be conducted at The Pennsylvania State University Children s Hospital. The school of medicine and graduate education reside within the same institution. Peter Rogan, Ph.D. (Human Genetics), and Joanna Floros, Ph.D. (Professor of Cellular and Molecular Biology), will function as co-sponsors. Dr. Towbin, M.D., (Director of Molecular Cardiology at Baylor Children's Hospital) will be a consultant contributing direct expertise within the field of molecular cardiology.